Programmed cell death is a crucial feature of the innate immune response to pathogens, serving to isolate and eradicate infected cells, preventing spread of infection. Viruses, as obligate intracellular pathogens, must effectively modulate the activation and signaling of these pathways in infected cells to prolong cellular survival for completion of viral replication. Murine cytomegalovirus (MCMV) represents a genetically tractable small animal model for analysis of viral and host factors and their contribution to the natural history of cytomegalovirus infection. MCMV employs cell death suppressors to modulate infected cell survival. These studies aim to utilize the MCMV model for understanding the mechanism of the MCMV M45 and the relative roles of M36 and M38.5 in modulation of the host innate immune system and programmed cell death pathways. Although M45 is a critical determinant of cell tropism and viral pathogenesis, it is currently unknown how M45 functions in these processes. Using a combination of molecular, virological, genetic, and immunologic techniques, these studies are designed to provide a comprehensive analysis of the function of M45 to protect from programmed cell death and activate the NF-kB pathway. With mechanism in hand, these studies will go on to determine the relative role(s) of M36, M38.5 and M45 in viral pathogenesis using the natural mouse host. Characterization of these virus-cell interactions will provide a better understanding of herpesvirus modulation of host immune responses, and may shed new light on conserved mechanisms of viral immune evasion that will apply to human CMV pathogenesis. Chronic and persistent viruses present a real and growing problem for uncompromised individuals. Many of these pathogens, especially herpesviruses, use conserved mechanisms to evade and manipulate the host immune response to establish and maintain life-long infections. The purpose of this application is to characterize a newly appreciated mechanism by which MCMV modulates cell death to evade the host innate immune response in order to replicate, disseminate, and establish chronic infection of its natural host. Elucidation of this molecular mechanism will provide a better understanding of herpesvirus biology, and may provide a unique target for therapeutic intervention at the earliest stages of primary infection